PROJECT SUMMARY Acute kidney injury (AKI) is one of the major manifestations of kidney disease. AKI's importance is underscored by recent studies reporting that its incidence is increasing. AKI disproportionately affects those with chronic kidney disease (CKD), so it is compelling to embed the investigation of AKI in the largest and most comprehensive prospective cohort study of CKD in the US, the Chronic Renal Insufficiency Cohort (CRIC) study. We propose to comprehensively evaluate all inpatient hospital records for all enrollees in CRIC Phases 3 and 4 (from 2013-2021) to identify episodes AKI, define their severity and examine their sequelae. CRIC was launched over a dozen years ago as a study of the natural history of CKD. It now offers an under-utilized but potentially unmatched opportunity to advance our understanding of the role AKI plays in shaping the natural history of CKD. Particularly valuable is the availability of research protocol-driven collection of data and biospecimens both before and after episodes of hospitalized AKI. Our Specific Aims are: 1) to evaluate the associations of hospitalized AKI and its severity with subsequent rate of loss of renal function after taking into account pre-AKI estimated glomerular filtration rate (eGFR) slope and pre-AKI proteinuria level; 2) to evaluate the associations of hospitalized AKI and its severity with change in proteinuria and to assess the relation between post-AKI proteinuria level and subsequent CKD progression; 3) to define the risk of future cardiovascular events associated with hospitalized AKI and its severity; 4) to determine the association of hospitalized AKI with changes in levels of biomarkers of injury, inflammation and fibrosis. Compared with all the other studies based on observational data now published in the literature, ours will have a much more rigorous experimental design, greatly reducing residual confounding and other biases. Our findings may challenge the current reigning paradigm that mild to moderate episodes of AKI worsen the course/outcome of CKD.